Cited by 1,140Amyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatmentsHereditary Neurological Disorders

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Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis

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Yamanaka, Koji, Chun, Seung Joo, Boillee, Severine, Fujimori-Tonou, Noriko, Yamashita, Hirofumi, Gutmann, David H, Takahashi, Ryosuke, Misawa, Hidemi, Cleveland, Don W·2008·Nature Neuroscience

DOI 10.1038/nn2047PMC PMC3137510

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Abstract

Dominant mutations in superoxide dismutase cause amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease that is characterized by the loss of motor neurons. Using mice carrying a deletable mutant gene, diminished mutant expression in astrocytes did not affect onset, but delayed microglial activation and sharply slowed later disease progression. These findings demonstrate that mutant astrocytes are viable targets for therapies for slowing the progression of non-cell autonomous killing of motor neurons in ALS.

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Background
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BackgroundResult
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Background
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Background
Role of FK506 Binding Proteins in Neurodegenerative Disorders
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Background
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Background
Imaging of glial cell morphology, SOD1 distribution and elemental composition in the brainstem and hippocampus of the ALS hSOD1G93A rat
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“From ongoing studies of ALS, it is now appreciated that this is a non-cell autonomous disease, where glia and neurons both play critical roles in disease progression (Yamanaka et al., 2008).”
Background
Dysfunction of the oligodendrocytes in amyotrophic lateral sclerosis
Gong, Z., Ba, L., & Zhang, M. (2022) · Journal of Biomedical Research · doi:10.7555/jbr.36.20220009 · Cited by 21
Astrocyte Immune Functions and Glaucoma
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“The neurodegenerative astrocytes are an important driver of various neurological diseases, including Alzheimer’s disease [4], Parkinson’s disease [5], Huntington’s disease [6], amyotrophic lateral sclerosis [7], and multiple sclerosis [8].”
Background
An in vitro model for studying CNS white matter: functional properties and experimental approaches
Bijland, S., Thomson, G., Euston, M., Michail, K., Thümmler, K., Mücklisch, S., Crawford, C. L., Barnett, S. C., McLaughlin, M., Anderson, T. J., et al. (2019) · F1000Research · doi:10.12688/f1000research.16802.1 · Cited by 17
“Conversely, ‘activated’ microglia and astrocytes can contribute to disease pathogenesis and injury to myelinated fibers, as in mouse models of motor neuron disease (Beers et al., 2006; Boillée et al., 2006; Hall et al., 1998; Nagai et al., 2007; Yamanaka et al., 2008), the leukodystrophies (Ip et al.”
Background
Amyotrophic lateral sclerosis
(2023) · Advances in magnetic resonance technology and applications · doi:10.1016/b978-0-323-91771-1.00016-2 · Cited by 19
Neurological and psychiatric disorders as a neuroglial failure.
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“On the other hand, several previous studies have proven the non-cell autonomous pathway in which reactive astrocytes contribute to motor neuronal damage in ALS [52, 53].”
The critical role of membralin in postnatal motor neuron survival and disease
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Mahogunin ring finger 1 confers cytoprotection against mutant SOD1 aggresomes and is defective in an ALS mouse model
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“, 2007) (Yamanaka et al., 2008) and from the patients with sporadic ALS (Haidet-Phillips et al.”
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“In the last decades, advances have come to suggest a critical role of neuroglial cross-talk and related microenvironmental modulation during neurodegenerative disorders [7, 19, 20].”
Background
The induction of Per1 expression by the combined treatment with glutamate, 5-hydroxytriptamine and dopamine initiates a ripple effect on Bmal1 and Cry1 mRNA expression via the ERK signaling pathway in cultured rat spinal astrocytes
Morioka, N., Sugimoto, T., Sato, K., Okazaki, S., Saeki, M., Hisaoka‐Nakashima, K., & Nakata, Y. (2015) · Neurochemistry International · doi:10.1016/j.neuint.2015.06.013 · Cited by 18
Effects of facial nerve axotomy on Th2- and Th1-associated chemokine expression in the facial motor nucleus of wild-type and presymptomatic mSOD1 mice
Wainwright, D. A., Xin, J., Mesnard, N. A., Politis, C. M., Sanders, V. M., & Jones, K. J. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2009.09.009 · Cited by 18
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Nefussy, B., & Drory, V. E. (2010) · The EPMA Journal · doi:10.1007/s13167-010-0027-0 · Cited by 18
“It has also been demonstrated that selective reduction in mutant SOD1 expression within microglia [68, 69] and astrocytes [70] significantly slows disease progression, but does not affect the timing of disease onset.”
Background
ALS-linked SOD1 in glial cells enhances ß-N-Methylamino L-Alanine (BMAA)-induced toxicity in Drosophila
Islam, R., Kumimoto, E. L., Bao, H., & Zhang, B. (2012) · F1000Research · doi:10.12688/f1000research.1-47.v1 · Cited by 18
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Kumar, M., Nguyen, T. P. N., Milanese, M., & Bonanno, G. (2022) · Biomolecules · doi:10.3390/biom12030344 · Cited by 20
“In particular, astrocytes have a detrimental role in ALS progression [102,103] with several mechanisms, including excitotoxicity, altered astrocyte metabolism, inflammation, and oxidative stress [104–107].”
Background
Stem cells and the ALS neurologist
Maragakis, N. J. (2010) · Amyotrophic Lateral Sclerosis · doi:10.3109/17482968.2010.489116 · Cited by 17
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A high-throughput screen to identify inhibitors of SOD1 transcription
Wright, P. D. (2012) · Frontiers in Bioscience-Elite · doi:10.2741/e584 · Cited by 18
“These include intraventricular administration of SOD1 antisense oligonucleotides (11), lentiviral delivery of SOD1 siRNA (12), immunization with misfolded SOD1 protein (which lowers mutant SOD1 levels in the spinal cord) (13) and the use of Cre/loxP recombinase technology to reduce SOD1 expression in specific neural c…”
Background
Immunoglobulins G from Sera of Amyotrophic Lateral Sclerosis Patients Induce Oxidative Stress and Upregulation of Antioxidative System in BV-2 Microglial Cell Line
Milosevic, M. M., Milicevic, K. D., Bozic, I. D., Lavrnja, I. C., Stevanović, I. D., Bijelić, D. D., Dubaić, M., Zivkovic, I. P., Stević, Z., Giniatullin, R. A., et al. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01619 · Cited by 17
“However, the late phase of disease progression in an animal model was slowed by selective excision of human mutant superoxide dismutase 1 SOD1 or Cu/ZnSOD gene from microglia and macrophage lineages, even when neurons are expressing high levels of the mutant gene (17) and diminished expression of mutant gene in astroc…”
Background
Endocannabinoids and amyotrophic lateral sclerosis
de Lago, E., Moreno‐Martet, M., Espejo‐Porras, F., & Fernández‐Ruíz, J. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-417041-4.00005-9 · Cited by 17
Constitutive downregulation protein kinase C epsilon in hSOD1G93A astrocytes influences mGluR5 signaling and the regulation of glutamate uptake
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“Deletion of mutant SOD1 specifically in astrocytes has been shown to delay microglial activation, disease onset and progression (Yamanaka et al., 2008; Wang, Gutmann, & Roos, 2011).”
Background
Predicting disease specific spinal motor neurons and glia in sporadic ALS
Dachet, F., Liu, J., Ravits, J., & Song, F. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104523 · Cited by 16
Inflammatory cytokines increase mitochondrial damage in motoneuronal cells expressing mutant SOD1
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“Misfolded SOD1 inclusions were identified in different glial cells of sALS and fALS patients (Forsberg et al., 2011) and selective deletion of mutant SOD1 expression in astrocytes retarded disease progression in a mouse model (Yamanaka et al., 2008).”
Background
Divergent functional outcomes of NLRP3 blockade downstream of multi-inflammasome activation: therapeutic implications for ALS
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“, 1998), and these responses become more severe as the disease progresses (Alexianu et al., 2001; Chiu et al., 2009; Yamanaka et al., 2008).”
The Kynurenine Pathway
Chen, Y., & Guillemi, G. (2012) · InTech eBooks · doi:10.5772/32332 · Cited by 16
“Hence, the loss of normal astrocytes in ALS would be detrimental to motor neurons and could exacerbate disease progression in ALS (Yamanaka et al. 2008).”
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“However, more recent work from the Cleveland lab demonstrated that if the pathogenic SOD1 mutant protein was diminished in astrocytes that disease progression and microglial activation were slowed (Yamanaka et al., 2008).”
High content analysis in amyotrophic lateral sclerosis
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Pre-symptomatic alterations in subcellular βCGRP distribution in motor neurons precede astrogliosis in ALS mice
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In FUS[1−359]‐tg mice O,S-dibenzoyl thiamine reduces muscle atrophy, decreases glycogen synthase kinase 3 beta, and normalizes the metabolome
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“Evidence from animal models indicate that astrocytes contribute to motoneuron (MN) degeneration and are important players in the onset and progression of ALS (Clement et al., 2003; Lepore et al., 2008; Yamanaka et al., 2008; Ilieva et al., 2009; Papadeas et al., 2011; Wang et al., 2011; van Zundert et al., 2012; Qian…”
Background
Umbilical cord mesenchymal stem cell-conditioned medium inhibits microglial activation to ameliorate neuroinflammation in amyotrophic lateral sclerosis mice and cell models
Tang, J., Kang, Y., Zhou, Y., Chen, Q., Lan, J., Liu, X., & Peng, Y. (2023) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2023.110760 · Cited by 16
“…et al., 2009) or astrocytes (Wang et al., 2011), performing wild-type microglia transplantation (Clement et al., 2003), or inhibiting astrogliosis (Yamanaka et al., 2008) all significantly extend the survival times of ALS mouse models, suggesting that abnormal microglial and astrocytic cell…”
Background
pTDP-43 levels correlate with cell type–specific molecular alterations in the prefrontal cortex of C9orf72 ALS/FTD patients
Wang, H. V., Xiang, J., Yuan, C., Veire, A. M., Gendron, T. F., Murray, M. E., Tansey, M. G., Hu, J., Gearing, M., Glass, J. D., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2419818122 · Cited by 15
Dual Role of Lysophosphatidic Acid Receptor 2 (LPA2) in Amyotrophic Lateral Sclerosis
Puigdomenech, M., Martínez‐Muriana, A., Andrés‐Benito, P., Ferrer, I., Chun, J. J. M., & López‐Vales, R. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.600872 · Cited by 16
“A common feature of ALS and other neurological disorders is the occurrence of an inflammatory response in the central nervous system (CNS), peripheral nervous system (PNS), and muscles (Nagai et al., 2007; Yamanaka et al., 2008; Frakes et al., 2014; De Virgilio et al., 2016; Newcombe et al., 2018; Bright et al., 2019).”
Background
Prognostic role of “prion-like propagation” in SOD1-linked familial ALS: an alternative view
Sugaya, K., & Nakano, I. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00359 · Cited by 16
Acute glial activation by stab injuries does not lead to overt damage or motor neuron degeneration in the G93A mutant SOD1 rat model of amyotrophic lateral sclerosis
Suzuki, M., Klein, S. M., Wetzel, E. A., Meyer, M., McHugh, J., Tork, C. A., Hayes, A. V., & Svendsen, C. N. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.12.004 · Cited by 15
“Moreover, reduction of mutant SOD1 expression in astrocytes by selective silencing, which was demonstrated by crossbreeding transgenic mice containing floxed mutant SOD1 with mice expressing Cre driven by GFAP promoter, also affected disease progression (Yamanaka et al., 2008).”
Effects of RAGE inhibition on the progression of the disease in hSOD1G93A ALS mice
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“Mitochondria-targeted catalase reverts the neurotoxicity of hSOD1G(9)(3)A astrocytes without extending the survival of ALSlinked mutant hSOD1 mice.”
Background
The BCL-2 family protein Bid is critical for pro-inflammatory signaling in astrocytes
König, H., Coughlan, K. S., Kinsella, S. M., Breen, B. A., & Prehn, J. H. M. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.06.008 · Cited by 14
“, 15 2007), thereby amplifying inflammation (Yamanaka et al., 2008).”
Could an Impairment in Local Translation of mRNAs in Glia be Contributing to Pathogenesis in ALS?
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Exploring Motor Neuron Diseases Using iPSC Platforms
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Mutant SOD1 knockdown in all cell types ameliorates disease in G85R SOD1 mice with a limited additional effect over knockdown restricted to motor neurons
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MethodResultInfluential
Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons
Aggarwal, T., Hoeber, J., Ivert, P., Vasylovska, S., & Kozlova, E. N. (2017) · Neurotherapeutics · doi:10.1007/s13311-016-0505-8 · Cited by 14
“In agreement with previous studies [11], we found that depletion of the astrocyte population from SOD1 cultures, increases MN survival.”
Spatiotemporal control of mitochondrial network dynamics in astroglial cells
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Astrocytic TGF-β1: detrimental factor in ALS
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Self-citation
Correction: Absence of Nrf2 or Its Selective Overexpression in Neurons and Muscle Does Not Affect Survival in ALS-Linked Mutant hSOD1 Mouse Models
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Elevated α5 integrin expression on myeloid cells in motor areas in amyotrophic lateral sclerosis is a therapeutic target
Chiot, A., Roemer, S. F., Ryner, L. C., Bogachuk, A. P., Emberley, K., Brownell, D., Jimenez, G. A., Leviten, M. W., Woltjer, R. L., Dickson, D. W., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2306731120 · Cited by 12
Edaravone in ALS
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“Recently, it has been shown that motor neuron death in mutant SOD1 ALS mouse models is non-cell autonomous (Boillee et al., 2006; Yamanaka et al., 2008).”
Self-citation
NR1D1 downregulation in astrocytes induces a phenotype that is detrimental to cocultured motor neurons
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The distribution and function of GDE2, a regulator of spinal motor neuron survival, are disrupted in Amyotrophic Lateral Sclerosis
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Astrocytic K+ clearance during disease progression in amyotrophic lateral sclerosis
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Background
TDP-43 modification in the hSOD1G93Aamyotrophic lateral sclerosis mouse model
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“790,791 Besides the 5-HT2R, the 5-HT4R is of interest in modulating neuroin ﬂ ammation in ALS.”
The Serotonergic System and Amyotrophic Lateral Sclerosis: A Review of Current Evidence
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“Mutant astrocytes (loxSOD1G37R) in turn enhance microglial activation (microgliosis), while deletion of mutant SOD1 from astrocytes suppresses microglial activation and slows later disease progression (Yamanaka et al. 2008).”
Background
Neuronal Circuit Dysfunction in Amyotrophic Lateral Sclerosis
Salzinger, A., Ramesh, V., Sharma, S. D., Chandran, S., & Selvaraj, B. T. (2024) · Cells · doi:10.3390/cells13100792 · Cited by 14
“Selective removal of mutant SOD1 in astrocytes [175], microglia [176], and oligodendrocytes [177] slowed disease progression.”
Background
Glial phagocytosis for synapse and toxic proteins in neurodegenerative diseases
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“Astrocytes carrying mutant SOD1 play a particularly detrimental role in the late stages of ALS [75, 76].”
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Screening for inhibitors of the SOD1 gene promoter: Pyrimethamine does not reduce SOD1 levels in cell and animal models
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“Reduction of levels of mutant SOD1 in motor neurons delays onset of paralysis in transgenic ALS mice [16] while diminished levels of mutant SOD1 in astrocytes and microglial cells delays microglial activation and slows disease progression after onset [17].”
Background
Amyotrophic lateral sclerosis models derived from human embryonic stem cells with different superoxide dismutase 1 mutations exhibit differential drug responses
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“Astrocytes are additionally implicated in MN death by secretion of neurotoxic factors (Wada et al., 2012) (Yamanaka et al., 2008) (Re et al., 2014) (Rojas et al., 2014) (Nagai et al., 2007).”
Background
Mucopolysaccharidosis IIIB confers enhanced neonatal intracranial transduction by AAV8 but not by 5, 9 or rh10
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GLT1 gene delivery based on bone marrow-derived cells ameliorates motor function and survival in a mouse model of ALS
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Up-regulation of ferritin ubiquitination in skeletal muscle of transgenic rats bearing the G93A hmSOD1 gene mutation
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Mammalian neuromuscular junctions: modern tools to monitor synaptic form and function
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Cortical hyperexcitability drives dying forward amyotrophic lateral sclerosis symptoms and pathology in mice
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Anti-Inflammatory Effects of Miyako Bidens pilosa in a Mouse Model of Amyotrophic Lateral Sclerosis and Lipopolysaccharide-Stimulated BV-2 Microglia
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“Indeed, the selective reduction in mutant SOD1 from microglia [7] or astrocytes [8] in mice using the Cre–Lox system slowed disease progression in SOD1G37R ALS model mice.”
Method
Trasplante de células troncales como terapia para la esclerosis lateral amiotrófica. Una mirada crítica
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“Los astrocitos contribuyen al daño de la motoneurona en el ratón mSOD in vivo e in vitro [10-12].”
Background
Fast Progression in Amyotrophic Lateral Sclerosis Is Associated With Greater TDP-43 Burden in Spinal Cord
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“This suggests a complex relationship between misfolded TDP-43 and cell death and dysfunction in LMN pools, potentially mediated by a pro-inflammatory environment (30), the astrocytic response to neuronal injury (31), or other processes, such as mitochondrial dysfunction (32).”
Background
Novel Indications for Benzodiazepine Antagonist Flumazenil in GABA Mediated Pathological Conditions of the Central Nervous System
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Quo vadis motor neuron disease?
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Temporospatial Analysis and New Players in the Immunology of Amyotrophic Lateral Sclerosis
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“Selective reduction of mSOD1 expression in microglia or astrocytes significantly extends the lifespan of ALS mice, thereby establishing a role for glial cells in MN degeneration [9,10].”
Background
Regional differences in the inflammatory and heat shock response in glia: implications for ALS
Clarke, B. E., Gil, R. S., Yip, J., Kalmár, B., & Greensmith, L. (2019) · Cell Stress and Chaperones · doi:10.1007/s12192-019-01005-y · Cited by 11
“Expression of SOD1G93A in glia does not result in elevated NO production or higher iNOS expression Glial cells are known to play a key role in determining the extent of motor neuron death in ALS (Boillee et al. 2006; Yamanaka et al. 2008).”
BackgroundInfluential
Existing and Emerging Metabolomic Tools for ALS Research
Germeys, C., Vandoorne, T., Bercier, V., & Bosch, L. V. D. (2019) · Genes · doi:10.3390/genes10121011 · Cited by 12
An mTOR-independent Macroautophagy Activator Ameliorates Tauopathy and Prionopathy Neurodegeneration PhenotypesPreprint
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Parkinson’s disease, epilepsy, and amyotrophic lateral sclerosis—emerging role of AMPA and kainate subtypes of ionotropic glutamate receptors
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Authors: Yamanaka, K., Chun, S. J., Boillee, S., Fujimori-Tonou, N., Yamashita, H., Gutmann, D. H., Takahashi, R., Misawa, H., & Cleveland, D. W.
Affiliations: University of California San Diego (US)
RIKEN Center for Brain Science (JP)
Corresponding author: Yamanaka, Koji
Cleveland, Don W
ORCID: Yamanaka, Koji
Yamashita, Hirofumi
Gutmann, David H
Cleveland, Don W
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2008-02-03
Volume: 11
Issue: 3
Pages: 251-253
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/nn2047
PMC: PMC3137510
OpenAlex: W2068147651
Cited by: 1,140
References: 15
Citations by year: 2026: 29 · 2025: 30 · 2024: 40 · 2023: 68 · 2022: 50 · 2021: 46 · 2020: 60 · 2019: 63 · 2018: 66 · 2017: 71 · 2016: 64 · 2015: 77 · 2014: 86 · 2013: 72 · 2012: 77
FWCI: 51.08
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Neuroscience (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of Neurological Disorders and Stroke (NS 27036, R37NS027036, R01NS027036)
Topics: Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords: astrocytes, amyotrophic lateral sclerosis, superoxide dismutase 1, SOD1 mutations, non-cell autonomous neurodegeneration, motor neuron degeneration, microglial activation, disease progression, astrocyte-targeted therapy, mouse model
MeSH terms: Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Astrocytes, Disease Models, Animal, Genes, Dominant, Glial Fibrillary Acidic Protein, Gliosis, Humans, Mice, Transgenic, Mutation, Nerve Degeneration, Nitric Oxide, Spinal Cord, Superoxide Dismutase, Genetic Therapy, Survival Rate, Cell Death, Microglia, Oxidative Stress, Disease Progression, Integrases, Mice, Nitric Oxide Synthase Type II

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Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis

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